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Document Page 406 β4 (residue Gly33 and Gln39). By such a conformation, residues Gln32, Gln34, and Glu37 have their side chains in the proposed binding surface. A β turn between 62 and 65 is folded in such a way that the charged groups of the residues Lys63, Glu64, and Lys65 present themselves on the proposed binding surface. Conformational arrangement via saltbridge scaffolds and other multiple hydrogen-bonding interactions stabilize the residue 102 to 113 loop, and orient the side chains of Lys103, Glu105, Asn107, and Asn108 in the proposed surface at the open end of the barrel. Similar arrangement places the side chains Arg11 and Gln15 in the proposed epitope. The amino and carboxy termini form a part of the proposed epitope, contributing the polar side chains of Arg4, Ser5, Asn7, Gln149, Ser152, and Ser153. Based on extensive analysis, we found that the structural elements like electrostatic and hydrogenbonding interactions in the loops between strands allow the polypeptide to adopt a conformation that enables an unusual concentration of polar and charged groups to be presented at the open end of the barrel. Such a cluster of charged residues around an area that is almost perpendicular to the barrel axis forms a hydrophilic patch with which IL-1 might bind to the receptor [42]. The core of the barrel, though probably not involved in binding, must nevertheless be important to the function of IL-1 because mutations within it reduce activity but not binding. We hypothesized that binding and cell proliferation through signal transduction involve separate regions of the IL-1 molecule; the surface polar loops are required for the binding and the core of the barrel is required for the physiological response. D. Three-Dimensional Structure of IL-1α The structure of IL-1α has been determined by x-ray crystallography [45] to a resolution of 2.7 Å in space group P2 1. Its general fold is very similar to that of IL-1β, having the same central β barrel along with the adjoining loops (Figure 4a, b). The overall rms distance between 133 aligned Cα positions of IL- 1β and IL-1α is 1.8 Å (Figure 5). The major difference between the two molecules is an N-terminal extension of 8 residues beyond the N-terminus of IL-1β. This projection forms a short β strand (residues 6-10), the presence of which positions the N-terminus of IL-1α in an alternative conformation. It has been postulated that this conformation is responsible for the differences in binding of precursor IL-1α and β: while precursor and mature IL-1α bind to IL-1RI and elicit response, only processed IL-1β binds with the receptor. This suggests that the N-terminal region of IL-1 probably plays a role in receptor binding. Extra residues in the alternate conformation of immature IL-1β serve to inhibit the receptor binding and thereby the biological activity. In contrast to IL-1β, IL-1α incorporates two other secondary structural elements: a short strand (residues 97–99) and about two turns of a 3 10 helix (residues 101–105), neither have been shown to be important in the function of the molecule. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_406.html [4/5/2004 5:44:45 PM]
Document Figure 4 (a) Stereo diagram of the secondary structural elements of IL-1α. Produced by Molscript [106]. (b) Stereo plot of all the atoms of IL-1α viewed parallel to the axis of the barrel. E. Three-Dimensional Structure of IL-1Ra Page 407 The x-ray structure of IL-1Ra was first reported in 1994 [47] and has since been solved by x-ray crystallography and NMR by several different laboratories [46–49]. Again, this molecule possesses the characteristic trefoil fold (Figure 6a) and similar tertiary structures (Figure 6b). The structure is similar to that of IL-1α and IL-1β with an rms deviation of 1.8 and 1.42 Å, respectively, when considering their Cα positions (Figure 7a). Structural superposition of these three molecules shows a common trefoil core (Figure 7b). In the absence of receptor substrate complexes, the comparison of all three structures combined with mutational studies (see below) is invaluable in obtaining a model of the regions http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_407.html (1 of 2) [4/5/2004 5:45:02 PM]
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Document D ddI, 152 tumour necrosis
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